A Biomimetic Autophagosomes-Based Nanovaccine Boosts Anticancer Immunity.

Personalized cancer vaccines based on tumor cell lysates offer promise for cancer immunotherapy yet fail to elicit a robust therapeutic effect due to the weak immunogenicity of tumor antigens. Autophagosomes, obtained from pleural effusions and ascites of cancer patients, have been identified as abundant reservoirs of tumor neoantigens that exhibit heightened immunogenicity. However, their potential as personalized cancer vaccines have been constrained by suboptimal lymphatic-targeting performances and challenges in antigen-presenting cell endocytosis. Here,a reinforced biomimetic autophagosome-based (BAPs) nanovaccine generated by precisely amalgamating autophagosome-derived neoantigens and two types of adjuvants capable of targeting lymph nodes is developed to potently elicit antitumor immunity. The redox-responsive BAPs facilitate cytosolic vaccine opening within antigen-presenting cells, thereby exposing adjuvants and antigens to stimulate a strong immune response. BAPs evoke broad-spectrum T-cell responses, culminating in the effective eradication of 71.4% of established tumors. Notably, BAPs vaccination triggers enduring T-cell responses that confer robust protection, with 100% of mice shielded against tumor rechallenge and a significant reduction in tumor incidence by 87.5%. Furthermore, BAPs synergize with checkpoint blockade therapy to inhibit tumor growth in the poorly immunogenic breast cancer model. The biomimetic approach presents a powerful nanovaccine formula with high versatility for personalized cancer immunotherapy.

Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression.

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth-by 100 to 140 times-in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.

Interactions between nanoparticles and lymphatic systems: Mechanisms and applications in drug delivery.

The lymphatic system has garnered significant attention in drug delivery research due to the advantages it offers, such as enhancing systemic exposure and enabling lymph node targeting for nanomedicines via the lymphatic delivery route. The journey of drug carriers involves transport from the administration site to the lymphatic vessels, traversing the lymph before entering the bloodstream or targeting specific lymph nodes. However, the anatomical and physiological barriers of the lymphatic system play a pivotal role in influencing the behavior and efficiency of carriers. To expedite research and subsequent clinical translation, this review begins by introducing the composition and classification of the lymphatic system. Subsequently, we explore the routes and mechanisms through which nanoparticles enter lymphatic vessels and lymph nodes. The review further delves into the interactions between nanomedicine and body fluids at the administration site or within lymphatic vessels. Finally, we provide a comprehensive overview of recent advancements in lymphatic delivery systems, addressing the challenges and opportunities inherent in current systems for delivering macromolecules and vaccines.

Orchestrating antigen delivery and presentation efficiency in lymph node by nanoparticle shape for immune response.

Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4+ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8+ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

Enhanced Codelivery of Gefitinib and Azacitidine for Treatment of Metastatic-Resistant Lung Cancer Using Biodegradable Lipid Nanoparticles.

Lung cancer is a formidable challenge in clinical practice owing to its metastatic nature and resistance to conventional treatments. The codelivery of anticancer agents offers a potential solution to overcome resistance and minimize systemic toxicity. The encapsulation of these agents within nanostructured lipid carriers (NLCs) provides a promising strategy to enhance lymphatic delivery and reduce the risk of relapse. This study aimed to develop an NLC formulation loaded with Gefitinib and Azacitidine (GEF-AZT-NLC) for the treatment of metastatic-resistant lung cancer. The physicochemical properties of the formulations were characterized, and in vitro drug release was evaluated using the dialysis bag method. The cytotoxic activity of the GEF-AZT-NLC formulations was assessed on a lung cancer cell line, and hemocompatibility was evaluated using suspended red blood cells. The prepared formulations exhibited nanoscale size (235-272 nm) and negative zeta potential values (-15 to -31 mV). In vitro study revealed that the GEF-AZT-NLC formulation retained more than 20% and 60% of GEF and AZT, respectively, at the end of the experiment. Hemocompatibility study demonstrated the safety of the formulation for therapeutic use, while cytotoxicity studies suggested that the encapsulation of both anticancer agents within NLCs could be advantageous in treating resistant cancer cells. In conclusion, the GEF-AZT-NLC formulation developed in this study holds promise as a potential therapeutic tool for treating metastatic-resistant lung cancer.

Assembly of nanostructured lipid carriers loaded gefitinib and simvastatin as hybrid therapy for metastatic breast cancer: Codelivery and repurposing approach.

Breast cancer represents a life-threatening problem globally. The major challenge in the clinical setting is the management of cancer resistance and metastasis. Hybrid therapy can affect several cellular targets involved in carcinogenesis with a lessening of adverse effects. Therefore, the current study aims to assemble, and optimize a hybrid of gefitinib (GFT) and simvastatin (SIM)-loaded nanostructured lipid carrier (GFT/SIM-NLC) to combat metastatic and drug-resistant breast cancer. GFT/SIM-NLC cargos were prepared using design of experiments to investigate the impact of poloxamer-188 and fatty acids concentrations on the physicochemical and pharmaceutical behavior properties of NLC. Additionally, the biosafety of the prepared GFT/SIM-NLC was studied using a fresh blood sample. Afterward, the optimized formulation was subjected to an MTT assay to study the cytotoxic activity of GFT/SIM-NLC compared to free GFT/SIM using an MCF-7 cell line as a surrogate model for breast cancer. The present results revealed that the particle size of the prepared NLC ranged from (209 to 410 nm) with a negative zeta potential value ranging from (-17.2 to -23.9 mV). Moreover, the optimized GFT/SIM-NLC formulation showed favorable physicochemical properties and promising lymphatic delivery cargos. A biosafety study indicates that the prepared NLC has a gentle effect on erythrocyte hemolysis. Cytotoxicity studies revealed that GFT/SIM-NLC enhanced the killing of the MCF-7 cell line compared to free GFT/SIM. This study concluded that the hybrid therapy of GFT/SIM-NLC is a potential approach to combat metastatic and drug-resistant breast cancer.

Surface-modified nanoparticles of docetaxel for chemotherapy of lung cancer: An intravenous to oral switch.

Despite being potent, the marketed formulations of Docetaxel (DX) are associated with numerous side effects and are meant for intravenous administration. Advanced pharmaceutical nanotechnology has a significant potential to facilitate the 'intravenous (i.v) to oral switch'. The present research work deals with the development of an orally administrable, folate-receptor-targeted Nanostructured lipid carriers (NLCs) of DX (FA-DX-NLCs) for facilitating oral chemotherapy of lung cancer while overcoming the bioavailability and toxicity issues. The nanoformulation prepared to employ high-pressure homogenization and lyophilization, was evaluated and statistically analyzed for various in-vitro and in-vivo formulation characteristics. The lyophilized nanoparticles were observed to be spherical with a particle size of 183.4 ± 2.13 (D90), Pdi of 0.358 ± 0.03, % EE of 82.41 ± 2.44, % DL of 4.41 ± 0.54 and a zeta potential of -3.3 ± 0.7 mv. The increased oral in-vivo bioavailability of DX was evident from the plasma-concentration area under the time curve (AUC0-t), which was âˆ¼ 27-fold greater for FA-DX-NLCs as compared to DX suspension. The orally administered FA-DX-NLCs exhibited excellent antitumor efficacy in a pre-clinical model of lung carcinoma. Tumor staging, histopathology, and immunostaining of the tumors suggested greater anti-proliferative, apoptotic, anti-metastatic, and anti-angiogenic potential as compared to DX-suspension. The pre-clinical toxicity studies affirmed the excellent safety and bio-compatibility of FA-DX-NLCs. The research work presents immense translational potential for switching the DX-based chemotherapy for lung cancer from 'hospital to home.'

Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons.

Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules.

Nanoparticles for Lymph Node-Directed Delivery.

Lymph nodes are organs that control immune cells and provide a major pathway for primary tumors to metastasize. A nanoparticles-based strategy has several advantages that make it suitable for achieving effective lymphatic delivery. First, the size of nanoparticles can be tailored to meet a size range appropriate for lymphatic migration. In addition, functionalized nanoparticles can target cells of interest for delivery of drugs or imaging probes. Existing lymph node contrast agents map all lymph nodes regardless of metastasis status; however, by using nanoparticles, it is possible to selectively target lymphatic metastases. Moreover, using functionalized nanoparticles, it is possible to specifically deliver anticancer drugs to metastatic lymph nodes. In this review, we introduce the use of nanoparticles for lymphatic mapping, in particular highlighting design considerations for detecting metastatic lymph nodes. Furthermore, we assess trends in lymph node-targeting nanoparticles in clinical practice and suggest future directions for lymph node-targeting nanoparticles.

Self-nanoemulsifying drug delivery systems (SNEDDS) of anti-cancer drugs: a multifaceted nanoplatform for the enhancement of oral bioavailability.

OBJECTIVE: A significant problem faced by the health care industry today is that though there are numerous drugs available to tackle diseases like cancer, their intrinsic properties make it difficult to be delivered to patients in a feasible manner. One of the key players that have helped researchers overcome poor solubility and permeability of drugs is Nanotechnology, this article further iterates on the same. SIGNIFICANCE: Nanotechnology is used as an umbrella term in pharmaceutics and describes under it multiple technologies. Upcoming nanotechnology is a Self Nanoemulsifying System which is considered to be a futuristic delivery system both due to its scientific simplicity and relative ease of patient delivery. METHODS: Self-Nano Emulsifying Drug Delivery Systems (SNEDDS) are homogenous lipidic concoctions containing the drug solubilized in the oil phase and surfactants. The choice of components depends on the physicochemical properties of the drugs, the solubilization capability of oils and the physiological fate of the drug. The article contains further details of various methodologies that have been adopted by scientists to formulate and optimize such systems in order to make anticancer drugs orally deliverable. RESULTS: The results that have been generated by scientists across the globe have been summarized in the article and all of the data supports the claim that SNEDDS significantly enhance the solubility and bioavailability of hydrophobic anticancer drugs. CONCLUSIONS: This article mainly provides the application of SNEDDS in cancer therapy and concludes to provide a step for the oral administration of several BCS class II and IV anticancer drugs.

Orchestrating antigen delivery and presentation efficiency in lymph node by nanoparticle shape for immune response

Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4+ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8+ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

Surface modified genistein phytosome for breast cancer treatment: In-vitro appraisal, pharmacokinetics, and in-vivo antitumor efficacy.

Based on phytosomes advantages over liposomes, hyaluronic acid (HA) with/out pegylated phospholipid was used to develop surface-modified genistein (Gen) phytosome as Gen pegylated hyaluophytosomes (G-PHA) and Gen hyaluophytosomes (G-HA) as novel delivery systems for breast cancer treatment. In this study, in-vitro characterization of G-HA and G-PHA shows PS 144.2 ±1.266 nm and 220.3 ±2.51 nm, ZP -30.9 ±0.75 and -32.06 ±0.305 respectively. Morphological elucidation shows HA covers the surface of G-HA and the presence of a transparent layer of PEG surrounding G-PHA. In-vitro release shows a significant slow Gen release from G-HA, and G-PHA compared to Gen solution and Gen phytosomes. In-vivo bioavailability data shows improvement in bioavailability for G-HA and G-PHA compared to Gen suspension (AUC0-t: 3.563 ± 0.067, 2.092 ± 0.058, 0.374 ± 0.085 µg/ml*h respectively). Therapeutic evaluation of the prepared targeted formulations was carried out by subcutaneous injection in an EAC-induced breast cancer model in mice. G-HA and G-PHA show a promising chemotherapeutic effect in terms of lowering the tumor size and tumor biomarkers (CEA: -34.6, -44.7 & CA15.3: -77.8, -81.6, respectively). This reduction in their values compared to Gen phytosomes, Gen suspension, and the control group is attributed to high Gen accumulation at the target organ owing to targeting properties of HA that are used in phytosomal surface modification in G-HA. Additionally, the presence of MPEG2000-DSPE in G-PHA tends to improve interstitium lymphatic drainage following SC administration, resulting in maximizing the therapeutic benefits of breast cancer despite the difference in pharmacokinetics behavior compared to G-HA. These formulations can be further studied for metastatic breast cancer.

Atazanavir-Concentrate Loaded Soft Gelatin Capsule for Enhanced Concentration in Plasma, Brain, Spleen, and Lymphatics.

This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain, spleen, and lymphatics beneficial in the significant reduction of viral load in HIV infection. For this purpose, ATV-concentrate in the presence and absence of Soluplus with corn oil, oleic acid, tween 80, and propylene glycol was developed. The developed ATV-concentrate was found to have enhanced dispersibility with no signs of precipitation after dilution with simulated G.I fluid as evident from particle size (16.49±0.32 nm) and PDI (0.217±0.02) analysis. The rheological and molecular docking studies explainedthe reduction of viscosity of SuATV-C due to the intermolecular H-bond between ATV and Soluplus that helps to retard crystallization. The shell of the soft gelatin capsule retains its integrity when subjected to a folding endurance test on a texture analyzer depicting that the concentrate did not affect the integrity of the soft gelatin capsule shell. An ex vivo and in vivo pharmacokinetic study in rats revealed that the SuATV-C soft gelatin capsule (SuATV-C SGC) indicated 2.9 fold improvement in rate and extent of permeation and absorption than that of ATV-suspension. The tissue distribution study also exhibited higher drug concentration in the brain (2.5 fold), lymph nodes (2.7 fold), and spleen (1.2 fold) administered with SuATV-C SGC, revealing the overwhelming influence of Soluplus and corn oil. In a nutshell, these studies demonstrated that SuATV-C SGC seems to have the potential to deliver an anti-retroviral drug to the viral sanctuaries for the better management of HIV.

Ovalbumin and Poly(i:c) Encapsulated Dendritic Cell-Targeted Nanoparticles for Immune Activation in the Small Intestinal Lymphatic System.

Here, antigen and adjuvant encapsulated dendritic cell-targeted nanoparticles for immune activation in the small intestinal lymphatic system to inhibit melanoma development are described. This strategy is demonstrated using chondroitin sulfate-coated nanoparticles (OPGMN) grafted with glycocholic acid and mannose for cationic liposomes encapsulated with ovalbumin as an antigen and polyinosine-polycytidylic acid as a cancer-specific adjuvant. OPGMN is absorbed in the gastrointestinal tract and delivered to the lymph nodes when orally administered. Oral delivery of OPGMN induces increased dendritic cell maturation compared to the intradermal route in the lymph node and induces T helper type 1 and type 2 responses, such as immunoglobulin G1 and G2c, interferon-gamma, and interleukin-2, in the blood. Repeated oral administration of OPGMN increases the population of CD3+ CD8+ T cells, CD44high CD62Llow memory T cells, and CD11b+ CD27+ natural killer cells in the blood. OPGMN completely prevents melanoma development in the B16F10-bearing C57BL/6 mouse model by reducing the population of CD4+ CD25+ Foxp3+ regulatory T cells in the blood. This strategy is expected to prevent the recurrence of tumors after various cancer treatments.

Enhanced T-Cell Priming and Improved Anti-Tumor Immunity through Lymphatic Delivery of Checkpoint Blockade Immunotherapy.

An infusion of checkpoint blockade immunotherapy (CBI) has revolutionized cancer treatments for some patients, but the majority of patients experience disappointing responses. Because adaptive immune responses are mounted by the concentrated assembly of antigens, immune cells, and mediators in the secluded and protective environment of draining lymph nodes (dLNs), we hypothesize that lymphatic delivery of CBI (αCTLA-4 and αPD-1) to tumor dLNs (tdLNs) improves anti-tumor responses over intravenous (i.v.) administration, and that vaccination against tumor associated antigen (TAA) further enhances these responses. Mono- and combination CBI were administered i.v. or through image-guided intradermal (i.d.) injection to reach tdLNs in vaccinated and unvaccinated animals bearing either primary or orthotopically metastasizing B16F10 melanoma. Vaccination and boost against TAA, Melan-A, was accomplished with virus-like particles (VLP) directed to tdLNs followed by VLP boost after CBI administration. Lymphatic delivery of CBIs reduced primary tumor size and metastatic tumor burden, alleviated the pro-tumorigenic immune environment, and improved survival over systemic administration of CBIs. Animals receiving CBIs lymphatically exhibited significantly enhanced survival over those receiving therapies administered partially or completely through systemic routes. By combining vaccination and CBI for effective T-cell priming in the protected environment of dLNs, anti-tumor responses may be improved.

Lipid Nanoparticle-Mediated Lymphatic Delivery of Immunostimulatory Nucleic Acids.

Lymphatic delivery of a vaccine can be achieved using a dendritic cell (DC)-targeted delivery system that can cause DC to migrate to lymph nodes upon activation by an adjuvant. Here, we designed a mannose-modified cationic lipid nanoparticle (M-NP) to deliver the nucleic acid adjuvant, polyinosinic:polycytidylic acid (PIC). PIC-loaded M-NP (PIC/M-NP) showed stable lipoplexes regardless of the ligand ratio and negligible cytotoxicity in bone marrow-derived DC. DC uptake of PIC/M-NP was demonstrated, and an increased mannose ligand ratio improved DC uptake efficiency. PIC/M-NP significantly promoted the maturation of bone marrow-derived DC, and local injection of PIC/M-NP to mice facilitated lymphatic delivery and activation (upon NP uptake) of DC. Our results support the potential of PIC/M-NP in delivering a nucleic acid adjuvant for the vaccination of antigens.

Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study.

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, -35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.

Bile acid transporter-mediated oral drug delivery.

Bile acids are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum at meals. Apical sodium-dependent bile acid transporter (ASBT), an ileal Na+-dependent transporter, plays the leading role of bile acid absorption into enterocytes, where bile acids are delivered to basolateral side by ileal bile acid binding protein (IBABP) and then released by organic solute transporter OSTα/ß. The absorbed bile acids are delivered to the liver via portal vein. In this process called "enterohepatic recycling", only 5% of the bile acid pool (~3 g in human) is excreted in feces, indicating the large recycling capacity and high transport efficacy of ASBT-mediated absorption. Therefore, bile acid transporter-mediated oral drug delivery has been regarded as a feasible and potential strategy to improve the oral bioavailability. This review introduces the key factors in enterohepatic recycling, especially the mechanism of bile acid uptake by ASBT, and the development of bile acid-based oral drug delivery for ASBT-targeting, including bile acid-based prodrugs, bile acid/drug electrostatic complexation and bile acid-containing nanocarriers. Furthermore, the specific transport pathways of bile acid in enterocytes are described and the recent finding of lymphatic delivery of bile acid-containing nanocarriers is discussed.

Dawn of lipid nanoparticles in lymph node targeting: Potential in cancer immunotherapy.

It is generally known that the lymph nodes (LNs) are important tissues in cancer immunotherapy. Therefore, delivering immune functional compounds to LNs is a useful strategy for enhancing cancer immunotherapy. Lipid-based nanocarriers have been widely used as delivery systems that target LNs, but lipid nanoparticle (LNP) technology has recently attracted increased interest. High levels of nucleic acids can be efficiently loaded in LNPs, they can be used to actively deliver nucleic acids into the cytoplasm, and they can be produced on an industrial scale. The use of microfluidic devices has been particularly valuable for producing small-sized LNPs, thus paving the way for successful LN targeting. In the review, we focus on the potential of LNP technology for targeting LNs.

Fabrication, optimization, and in vitro evaluation of docetaxel-loaded nanostructured lipid carriers for improved anticancer activity.

Lung cancer is the leading cause of cancer-related deaths in both men and women worldwide. It is the leading cancer killer in both men and women in every Ethnic Group. A major problem associated with chemotherapies against their lung cancer is the lack of selective toxicity, which results in a narrow therapeutic index thereby compromising clinical prognosis. To circumvent these challenges, the present investigation sought to develop a docetaxel-loaded nanostructured lipid carrier system (DTX-NLCS) for the treatment of lung cancer. A 3-factor/3-level Box-Behnken Design was applied to systematically optimize the DTX-NLCS parameters. The amount of drug, emulsifier concentration, and homogenization speed was selected as independent variables, while the particle size and % entrapment efficiency (%EE) were selected as dependent variables. The optimized batch parameters were 29.81 mg drug, 19.97% w/w emulsifier, and 13 200 (rpm) speed of homogenization with a mean particle size of 154.1 ± 3.13 nm and a mean %EE of 86.12 ± 3.48%. The in vitro lipolysis experiments revealed that the optimized DTX-NLCs were stabilized by 10% w/w PEG 4000 mono-stearate and exhibited an anti-lipolytic effect. Furthermore, the in vitro gastrointestinal stability studies (at pH-1.2, pH-4.5, pH-6.8, and pH-7.4) revealed that the optimized developed system could withstand various GI tract media. The in vitro dissolution studies depicted a pH-independent controlled-release consistent with the Weibull model. In vitro cytotoxicity studies using NCI-H460 cell lines further revealed that there was a reduction in IC50 values in the DTX-NLCS treated cells as compared to those treated with the pure drug, indicating an improved efficiency for the developed system.